Cannabis has been used medicinally for many years, and in Victorian times was a widely used component of prescription medicines. It was used as a hypnotic sedative for the treatment of “hysteria, delirium, epilepsy, nervous insomnia, migraine, pain and dysmenorrhoea”. Historically, cannabis was regarded by many physicians as unique; having the ability to counteract pain resistant to opioid analgesics, in conditions such as spinal cord injury, and other forms of neuropathic pain including pain and spasm in multiple sclerosis.
The use of cannabis continued until the middle of the twentieth century, when the recreational use of cannabis prompted legislation which resulted in the prohibition of its use. The utility of cannabis as a prescription medicine is now being re-evaluated. The discovery of specific cannabinoid receptors and new methods of administration have made it possible to extend the use of cannabis-based medicines to historic and novel indications.
The principle cannabinoid components present in herbal cannabis are the cannabinoid acids Δ9 tetrahydrocannabinolic acid (Δ9 THCA) and cannabidiolic acid (CBDA), with small amounts of the corresponding neutral cannabinoids, respectively Δ9 tetrahydrocannabinol (Δ9 THC) and cannabidiol (CBD). Cannabidiol was formerly regarded as an inactive constituent, however there is emerging evidence that it has pharmacological activity, which is different from that of Δ9 THC in several respects.
In addition to these major cannabinoids, herbal cannabis may contain lower levels of other minor cannabinoids. These may be intermediates in the biosynthesis of the major cannabinoids and hence exist at only low levels in the plant as they are constantly undergoing further biotransformation once they are formed. An example of such a cannabinoid is cannabigerol (CBG). Other minor cannabinoids may represent the end point of an alternative biosynthetic pathway to that leading to the formation of the major cannabinoids Δ9 THC and CBD. These cannabinoids are frequently relatively more abundant in the plant, an example being cannabichromene (CBC).
A special example of a minor cannabinoid that is the end point of a biosynthetic pathway is Δ9 Tetrahydrocannabivarin (Δ9 THCV). This compound is closely related to Δ9 THC, with the only difference in structure being the presence of a propyl (C3H7) side chain rather than a pentyl (C5H11) side chain on the aromatic ring. This compound usually accompanies Δ9 THC at a level of 1-2% of THC present. However in certain selectively bred varieties of cannabis Δ9 THCV can account for greater than 70% of total cannabinoids, with Δ9 THC being reduced to the level of a minor constituent.
Purified forms of certain of the cannabinoids present in herbal cannabis are useful as active pharmaceutical agents. For example, Δ9 THC (also known as dronabinol) has been approved by the Food and Drug Administration (FDA) for the control of nausea and vomiting associated with chemotherapy, and also shows potential pharmacological activity in the treatment of glaucoma, migraine headaches, anxiety, and as an analgesic. Cannabidiol, formerly regarded as an inactive constituent of cannabis, has, as aforesaid, itself shown promising pharmacological activity.
In the case of the minor cannabinoids, the difficulties in isolating the minor cannabinoids in a pure state and the absence of commercially available standards have restricted the investigation of the pharmacology of these compounds and their true therapeutic potential is unknown. Consequently it is of great interest to isolate sufficiently pure samples of these cannabinoids in the quantities required to permit pharmacological studies to be performed.
Purified forms of the cannabinoids and cannabinoid acids are also potentially useful as analytical standards, particularly in the characterisation of cannabis-derived medicines based on botanical drug substances prepared from herbal cannabis. 
Thus, there remains a need for purified forms of all of the cannabinoid acids and cannabinoids present in cannabis herb, including the major cannabinoids Δ9 THC and CBD and the minor cannabinoids.
Synthetic forms of certain of the cannabinoids, particularly Δ9 THC, CBD and CBN, are commercially available. However, synthetic cannabinoids are extremely expensive. Attention has therefore focussed on the purification of cannabinoids from plant material.
WO 02/32420 discloses a process for preparing, for example, Δ9-THC from plant material. It utilises CO2 extraction and ethanol precipitation to obtain “primary extracts” containing Δ9-THC and CBD, with reduced amounts of, for example, monoterpenes, sesquiterpenes, hydrocarbons, alkaloids, flavonoids and chlorophylls. The CBD is then converted to Δ9-THC by a catalysing reaction. The cannabinoids make up only approximately two-thirds of the composition and are therefore not substantially pure.
U.S. Pat. No. 6,403,126 discloses a process in which THC is removed from a cannabis extract using chromatography.
JP 3153625 discloses a method of producing an anti-allergic agent. In one example, dry seeds of cannabis are subjected to multiple extraction steps and multiple chromatographic steps.
Biochemical Medicine (1973, vol. 8, P. 341-344) discloses a multi-step extraction and purification process for producing Δ9-THC of unspecified purity.
ODCCP Bulletin on Narcotics (1976, Issue 4) discloses a method of isolating CBD, THC and CBN using preparative gas chromatography.
U.S. Pat. No. 6,365,416 describes a method of preparing Δ9 THC from plant material which involves extracting the plant material with a non-polar organic solvent, optionally subjecting the extract to a column chromatography step to produce a residue eluate, subjecting the extract or the residue eluate to a low pressure flash distillation to produce a distillate, optionally subjecting the distillate to a second flash distillation step, and subjecting the distillate to column chromotography, normal HPLC or reverse-phase HPLC. The process provides a product containing Δ9 THC in an amount greater than 90% by weight.
There remains a need for alternative purification processes which may be used to prepare purified forms of all cannabinoid and cannabinoid acid constituents of cannabis herb, including the cannabinoid acids Δ9 THCA and CBDA, the corresponding free cannabinoids Δ9 THC and CBD, and the minor cannabinoids. The present invention relates to such a purification process based on a simple combination of solvent extraction, chromatography and re-crystallisation steps. The process is simple, efficient and economic, and is capable of producing cannabinoids of high purity, whilst avoiding the need for preparatory HPLC.